CN102076345A - 顺铂配位化合物的液体组合物 - Google Patents
顺铂配位化合物的液体组合物 Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 150000001875 compounds Chemical class 0.000 title claims abstract description 17
- 239000007788 liquid Substances 0.000 title abstract description 8
- 229920001400 block copolymer Polymers 0.000 claims abstract description 19
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims abstract description 19
- 229960004316 cisplatin Drugs 0.000 claims abstract description 18
- 239000012530 fluid Substances 0.000 claims description 27
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- 125000001165 hydrophobic group Chemical group 0.000 claims description 4
- 150000005846 sugar alcohols Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 229920002643 polyglutamic acid Polymers 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108010020346 Polyglutamic Acid Proteins 0.000 description 4
- -1 carboxylate anion Chemical class 0.000 description 4
- 238000005227 gel permeation chromatography Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
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- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000001308 Fasciculation Diseases 0.000 description 1
- 206010028293 Muscle contractions involuntary Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- BBEAQIROQSPTKN-UHFFFAOYSA-N antipyrene Natural products C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
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- 238000006243 chemical reaction Methods 0.000 description 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
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Abstract
液体组合物，其特征在于，含有使顺铂与用聚乙二醇和聚谷氨酸形成的嵌段共聚物配位结合而成的高分子胶束，且pH为3.0～7.0。
Description
技术领域
本发明涉及稳定的顺铂配位化合物的液体组合物。
背景技术
顺铂(cis-Diamminedichloroplatinum(II)：顺二氯二氨合铂(II))在临床中是非常有效的抗癌剂，但已知其肾毒性等副作用非常强。因此，在给予顺铂前，在给药中以及给药后需要大量的输液。
为了解决这样的问题，发明了在使顺铂与用聚乙二醇和聚谷氨酸形成的嵌段共聚物配位结合而成的配位化合物。
现有技术文献
专利文献
专利文献1：WO02/26241号公报
发明内容
发明要解决的问题
本发明的目的在于，使包含使顺铂与用聚乙二醇和聚谷氨酸形成的嵌段共聚物配位结合而成的配位化合物的液体组合物稳定化。
本发明人为了希望得到使顺铂与用聚乙二醇与聚谷氨酸形成的嵌段共聚物配位结合而成的络合物的稳定化而积极研究，结果，发现在特定范围的pH中，可使上述络合物稳定化，从而完成本发明。
即，本发明包含以下方式。
(1)液体组合物，其是含有由式I或式II表示的嵌段共聚物和顺铂的配位化合物的液体组合物，特征在于，该液体组合物的pH为3.0～7.0，
(上式I以及II中，R1独立地表示氢原子或可以被官能团或取代基取代的烷基，A独立地表示NH、CO、R5(CH2)pR6或直接键合，其中，R5为O、OCO、OCONH、NHCO、NHCOO、NHCONH、CONH或COO，R6为NH或CO，而且，p为1～6的整数；R2独立地为氢原子、碱金属或烷基或芳烷基，R3独立地表示氢原子、羟基或疏水性残基，n表示110～340的整数，m表示20～80的整数。)
(2)如(1)所述的液体组合物，其特征在于，液体组合物的pH为4.0～6.0。
(3)如(1)或(2)所述的液体组合物，其特征在于，所述液体组合物进一步含有糖或者糖醇；
(4)如(3)所述的液体组合物，其特征在于，糖或糖醇为D-甘露糖醇；
(5)如(4)所述的液体组合物，其特征在于，液体组合物中的D-甘露糖醇的浓度为5％(W/V)。
具体实施方式
本发明中所述的嵌段共聚物与顺铂的配位化合物是指分子内的2个氯离子中的一个或两个被式I或式II表示的嵌段共聚物的羧酸根阴离子交换的化合物。作为本发明的配位化合物，优选顺铂的Pt与该共聚物的羧酸根阴离子的当量比(Pt/COO-)为0.3以上。
另外，本发明的配位化合物可在水性介质中形成高分子胶束。
本发明的由式I或式II所表示的嵌段共聚物中，作为R2中所述的疏水性基团，可举出：C8-16烷基羰基及C8-16烷基、苯基乙酰基及苄基、二苯基乙酰基及二苯甲基、芘磺酰基和芘基、金刚烷基、胆甾醇基等，但并不限定于这些基团。这些基团可以通过酰氯法或其它活性酯化法引入。这样的疏水性基团视情况而定，可起到提高水性介质中根据本发明的配位化合物的自缔合能力、即高分子胶束化能力的作用。
作为R1中所述的可被保护的官能团，可以举出：羟基、缩醛基、缩酮基、醛基、糖残基、马来酰亚胺基、羧基、氨基、硫醇基、活性酯基等。R1表示可以被保护的官能团取代的低级烷基情形下的亲水性链段可以依据例如WO96/33233、WO96/32434、WO97/06202所述的方法。
另外，对于本发明的由式I或式II所表示的嵌段共聚物，自不必说，n及m为平均值，特别优选以下的嵌段共聚物。
式中，n表示110～340的整数，特别优选200～340的整数，m表示20～80的整数，特别优选30～50的整数。
合成式I、I-a或II所示的嵌段共聚物的方法只要能够得到希望的嵌段共聚物就没有特别限定，例如，在合成I-a的情形下，以MeO-PEGOCH2CH2CH2HN2作为引发剂，以变成希望的m单元数的方式，在脱水的有机溶剂中，添加N-羧基-γ-苄基-L-谷氨酸酯并反应，使合成的嵌段共聚物的聚谷氨酸的侧链的苄基进行碱水解，由此可制得I-a。
本发明的液体组合物是指含有上述配位化合物、特别是高分子胶束的液体，包含制剂、制剂的原液、进行冷冻干燥前的液体。
本发明的有关物质在通过凝胶渗透色谱法(GPC)测定在水性介质中形成高分子胶束的嵌段共聚物与顺铂的配位化合物时以高分子胶束以外的峰表示，是指嵌段共聚物分解及/或高分子胶束崩散而出现的峰，其含量可以以GPC图中高分子胶束以外的面积在总面积中所占的百分率表示。
本发明的液体组合物的pH为在40℃下保存高分子胶束时的有关物质的产量为7％以下、优选5％以下、更优选3％以下的pH，该pH优选为3.0～7.0，更优选为4.0～6.0。
液体组合物只要在上述pH范围内就没有特别的限定，可以在含有配位化合物、特别是高分子胶束的液体中边搅拌边缓慢加入用于注射剂pH调节的添加剂例如盐酸、氢氧化钠、柠檬酸、柠檬酸钠、醋酸、酒石酸、氢氧化钾、碳酸氢钠、碳酸钠、乳酸、三乙醇胺、磷酸、磷酸氢二钠、磷酸二氢钠等来制备，在此，所谓含有高分子胶束的液体，只要嵌段共聚物与顺铂的配位键不断裂，就可以使用稀的缓冲液，特别优选水。
实施例
以下，通过实施例对本发明进行详细的说明，但这并不限定本发明的范围。
实施例1
高分子胶束的制备
将顺铂70g溶解于注射用水而形成的溶液、通过专利文献1所述的方法合成的共聚物和甲氧基聚乙二醇-聚谷氨酸共聚物、PEG-p(Glu)(PEG的平均分子量：12000，谷氨酸的平均残基数：40，谷氨酸侧链为羧酸)105g溶解于注射用水而形成的溶液混合，加入注射用水使总量为50L。使该溶液在37℃下反应3天。通过反复超滤(分级分子量：100000)对得到的溶液进行精制，然后浓缩，添加D-甘露糖醇和注射用水，制得高分子胶束溶液(以顺铂计相当于2.5mg/ml，含有5％的D-甘露糖醇)。
实施例2
高分子胶束的稳定性试验
在制备的高分子胶束溶液20ml(以顺铂计相当于2.5mg/ml，含有5％的D-甘露糖醇)中缓慢添加0.01mol/L盐酸或0.01mol/L氢氧化钠溶液、以及注射用水，调节pH为3.0、4.0、5.0、6.0、7.0或9.0，使总量为25ml。将各pH的溶液以每个6ml分别注入褐色样品瓶中，密封在5℃下保存。两天后，在下述条件下对有关物质的量进行测定，将剩余的样品瓶转移到40℃条件下，再保存20天。保存后，同样在下述条件下对有关物质的量进行测定。
(条件)
装置：Waters GPC system
色谱柱：Waters Ultrahydrogel 500，10μm，7.8Φ×300mm
柱温：约40℃的恒温
检测器：UV检测器(检测波长280nm)
移动相：将磷酸二氢钠(无水)2.87g、磷酸氢二钠·十二水合物0.24g以及氯化钠2.92g溶解于水中配制成1升溶液。
流速：约0.6ml/分钟
在5℃下保存2天后的有关物质的量的测定结果如表1所示，在40℃下保存20天后的有关物质的量的测定结果如表2所示。
表1
| 初期调整pH | 3.0 | 4.0 | 5.0 | 6.0 | 7.0 | 9.0 |
| 有关物质合计(％) | 1.6 | 1.1 | 0.6 | 0.46 | 0.46 | 1.16 |
表2
| 初期调整pH | 3.0 | 4.0 | 5.0 | 6.0 | 7.0 | 9.0 |
| 有关物质合计(％) | 6.8 | 2.7 | 1.9 | 2 | 5.75 | 75.63 |
由以上结果可知，即使在40℃保存20天这样的严酷条件下，在pH3.0～7.0之间、特别是pH4.0～6.0之间，含有形成高分子胶束的嵌段共聚物和顺铂的配位化合物的液体组合物极其稳定。
Claims (5)
1.液体组合物，其是含有由式I或式II表示的嵌段共聚物和顺铂的配位化合物的液体组合物，特征在于，该液体组合物的pH为3.0～7.0，
上式I以及II中，R1独立地表示氢原子或可以被官能团或取代基取代的烷基，A独立地表示NH、CO、R5(CH2)pR6或直接键合，其中，R5为O、OCO、OCONH、NHCO、NHCOO、NHCONH、CONH或COO，R6为NH或CO，而且，p为1～6的整数；R2独立地为氢原子、碱金属或烷基或芳烷基，R3独立地表示氢原子、羟基或疏水性残基，n表示110～340的整数，m表示20～80的整数。
2.权利要求1所述的液体组合物，其特征在于，所述液体组合物的pH为4.0～6.0。
3.权利要求1或2所述的液体组合物，其特征在于，所述液体组合物进一步含有糖或者糖醇。
4.权利要求3所述的液体组合物，其特征在于，所述糖或糖醇为D-甘露糖醇。
5.权利要求4所述的液体组合物，其特征在于，所述液体组合物中的D-甘露糖醇的浓度为5％(W/V)。
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| CN102604082A (zh) * | 2012-02-15 | 2012-07-25 | 中国科学院长春应用化学研究所 | 顺铂配合物及其制备方法 |
| CN103272244A (zh) * | 2013-01-21 | 2013-09-04 | 长春理工大学 | 一种药物键合物、制法及其在治疗肿瘤的应用 |
| CN108026271A (zh) * | 2015-09-14 | 2018-05-11 | 日本化药株式会社 | 6配位铂络合物的高分子偶联物 |
| CN109908084A (zh) * | 2019-04-11 | 2019-06-21 | 临沂大学 | 一种铂交联喜树碱前药胶束纳米药物及其制备方法和应用 |
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| JP2011105792A (ja) * | 2009-11-12 | 2011-06-02 | Japan Science & Technology Agency | ブロックコポリマー、ブロックコポリマー−金属錯体複合体、及びそれを用いた中空構造体キャリア |
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| WO1996032434A1 (fr) | 1995-04-14 | 1996-10-17 | Kazunori Kataoka | Oxydes de polyethylene ayant un groupe saccharide a une extremite et un groupe fonctionnel different a l'autre extremite, et procede pour produire lesdits oxydes de polyethylene |
| CN1085987C (zh) | 1995-04-19 | 2002-06-05 | 片冈一则 | 杂远螯嵌段共聚物及其制备方法 |
| NZ313769A (en) | 1995-08-10 | 2000-02-28 | Kazunori Kataoka | block polymer having a functional group presented on each end |
| CN100344293C (zh) | 2000-09-26 | 2007-10-24 | 株式会社东京大学Tlo | 包封顺铂的高分子微胶粒及其用途 |
| US7094810B2 (en) * | 2001-06-08 | 2006-08-22 | Labopharm, Inc. | pH-sensitive block copolymers for pharmaceutical compositions |
| JP2003012505A (ja) | 2001-07-06 | 2003-01-15 | Nano Career Kk | 薬物含有高分子ミセルの凍結乾燥 |
| JPWO2006057429A1 (ja) * | 2004-11-24 | 2008-06-05 | ナノキャリア株式会社 | ブロックコポリマーのモーフォロジーの変化方法 |
| JP5046957B2 (ja) * | 2005-12-05 | 2012-10-10 | ナノキャリア株式会社 | フッ素系有機溶媒を用いた薬物封入ポリマーミセルを含有する医薬組成物の製造方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102604082A (zh) * | 2012-02-15 | 2012-07-25 | 中国科学院长春应用化学研究所 | 顺铂配合物及其制备方法 |
| CN102604082B (zh) * | 2012-02-15 | 2013-12-11 | 中国科学院长春应用化学研究所 | 顺铂配合物及其制备方法 |
| CN103272244A (zh) * | 2013-01-21 | 2013-09-04 | 长春理工大学 | 一种药物键合物、制法及其在治疗肿瘤的应用 |
| CN108026271A (zh) * | 2015-09-14 | 2018-05-11 | 日本化药株式会社 | 6配位铂络合物的高分子偶联物 |
| CN108026271B (zh) * | 2015-09-14 | 2021-03-12 | 日本化药株式会社 | 6配位铂络合物的高分子偶联物 |
| CN109908084A (zh) * | 2019-04-11 | 2019-06-21 | 临沂大学 | 一种铂交联喜树碱前药胶束纳米药物及其制备方法和应用 |
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| JPWO2009157279A1 (ja) | 2011-12-08 |
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